Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion

Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion Hillard M. Lazarus and Selina Luger Ireland Cancer Center, University
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Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion Hillard M. Lazarus and Selina Luger Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia (ALL) is not clearcut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in complete remission (CR). Those considered to be at high risk for relapse often are considered for HSCT in first complete remission (CR1) while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor. In some patients who have a suitable histocompatible sibling, disease- or patient-related factors may override the potential benefit of allogeneic HSCT. Because many patients do not have a suitable histocompatible sibling, Would You Recommend Stem Cell Transplantation for Either of These Patients? Case 1: A 32-year-old woman with no significant past medical history presented to her physician with a 2- week history of abdominal discomfort, a 20-pound weight loss over 2 months, and hepatosplenomegaly. Laboratory studies revealed a white blood cell (WBC) count of 14,200/µL with circulating blasts expressing CD34, CD45, CD19 and CD20. Cytogenetics revealed a normal karyotype. The final diagnosis was pre B-cell acute lymphoblastic leukemia (ALL), Philadelphia-chromosome negative (Ph ). She was given induction therapy and attained a complete remission (CR). She has an HLA-identical brother. Case 2: A 64-year-old man was evaluated for a 4- month history of progressive cytopenias. Bone marrow exam showed extensive, diffuse infiltration by mostly small- and intermediate sized mononuclear cells that, on flow cytometry, expressed CD45 dim, CD38 and CD19 and the karyotype revealed t(4:11). The final diagnosis was pre-b cell ALL, Ph, with a t(4:11) karyotype abnormality. He was treated with daunorubicin, vincristine and prednisone. Repeat bone marrow study revealed persistent leukemia. The patient was believed to be refractory to induction therapy. He also had fever and typhlitis. He later was given highdose methotrexate, cytarabine, cyclophosphamide, vincristine, doxorubicin and dexamethasone. The bone marrow examination revealed no residual leukemia. He attained a CR and has an HLA-identical sister. one has to consider the relative merits of autologous transplantation versus use of an alternative allogeneic stem cell source, such as a matched-unrelated donor (MUD), umbilical cord blood (UCB) donor, or haploidentical donor. Deciding among these options in comparison to chemotherapy even in high-risk patients is difficult. In the review, the risks and benefits of these choices are discussed to determine whether and by what means to proceed to HSCT in adult patients with ALL who are in CR1. Presented are two patients with ALL and a discussion of how the data we provide would lead to a decision about the selection of therapy. Discussion Contrary to the excellent results achieved in pediatric patients, the outcomes for ALL in adult patients are disappointing. There is considerable evidence that the biologic and clinical characteristics of this disease change dramatically from childhood to adult age groups, including immunophenotype and karyotype. These differences must be recognized when making treatment recommendations for adult ALL patients. While in recent multicenter trials more than 90% of adult patients with ALL younger than 60 years attain CR, conventional chemotherapy is a long arduous process and will result in long-term survival in only one-third of patients. A number of prognostic factors identified at diagnosis are associated with low probability of cure in adult patients with ALL receiving conventional therapy. Such factors include high WBC count at diagnosis ( 30,000/µL for B-cell lineage and 100,000/µL for T-cell lineage), specific clonal cytogenetic abnormalities such as the presence of Ph, age older than 35 years, extramedullary disease and time to attain CR longer than 4 weeks, although the latter was not observed in the largest ALL study conducted in adults. 1 Adverse Factors The presence of the Ph chromosome affects the chance of remission after induction, as well as the risk of relapse, when using conventional chemotherapy. A recent publication by Moorman et al 2 described other karyotypes that portend a poor prognosis. Age remains an important prognostic factor. In many studies including the French proto- 444 American Society of Hematology col LALA-87, 3 age older than 35 years decreases the chance of remission as well as increases the risk of relapse in patients given conventional chemotherapy. In the international MRC-ECOG UKALLXII/E2993 trial, patients older than 35 years with high WBC counts at presentation had a dismal outcome when using conventional chemotherapy. 1 It remains unclear whether that outcome can be improved with transplantation. Molecular Monitoring Several investigators have introduced more sensitive molecular techniques such as clonal immunoglobulin or T- cell receptor gene rearrangements to detect minimal residual disease (MRD) that can accurately predict relapse in patients with ALL. 4 Pediatricians have recognized that molecular persistence of residual ALL at the end of induction chemotherapy or afterward effectively predicted relapse independent of other risk factors. 5,6 Molecular marker monitoring has been used less extensively in adult ALL but appears to be an extremely powerful tool that has yet to be exploited. Brüggemann and colleagues 7 of the German Multi-Center Study Group for Adult ALL reported that patients with standard-risk ALL who had a rapid decline in MRD within the first month of therapy had a 0% 3-year relapse rate while those with molecular persistence of ALL by week 16 of therapy had a 94% 3-year relapse rate (Figure 1). In a subset of patients treated on the MRC-ECOG adult ALL trial discussed above, detection of MRD (especially in the pre B-cell subtype) had prognostic significance. 8,9 In their hands, the detection of MRD by the completion of the second month of induction therapy appeared to be the optimal timepoint to ascertain ultimate prognosis. 8,9 The measurement of MRD has been incorporated into the successor MRC-ECOG led Intergroup trial in order to help restratify low-risk patients (based on clinical prognostic features) into those patients who now would be considered high-risk due to detection of MRD at the end of induction therapy. The use of this technique will require standardization for methodology when it is used in the clinical course of the patient. How allogeneic hematopoietic stem cell transplantation (HSCT) is affected by or impacts upon these risk factors has been less well studied. Although the risk of relapse decreases with allogeneic HSCT, the concomitant treatment-related mortality (TRM) eliminates the potential survival benefit. Doney et al 10 reported on 182 ALL patients with ALL in first CR (CR1) or beyond and found improved disease-free survival (DFS) and overall survival (OS) in younger patients and those in CR1. Allogeneic HSCT conferred similar OS and relapse rates for Ph + patients compared with those with normal cytogenetics supporting a graft-versus-leukemia (GVL) effect that is particularly beneficial in that group. Although other karyotypic abnormalities have been shown to portend a poor prognosis with conventional chemotherapy, 2 available data are insufficient to determine if there is a benefit to allogeneic HSCT in these patients. Gorin for the European Group for Blood and Marrow Transplantation (EBMT) 11 reviewed data on 1402 patients with ALL given allogeneic HSCT in CR1 and noted that time to transplant was a major prognostic factor. Of 414 patients who received transplants within 3 months after achieving CR, patient age, attainment of CR1 with 1 or more induction courses and recipient/donor sex combination predicted outcome. Patients with no unfavorable factors (age younger than 35 years, less than 1 induction course, female donor graft to male recipient) had a 3-year leukemia-free survival (LFS) of 56% compared with 48% for those with 1 adverse factor and 29% for 2 or 3 adverse factors. OS rates were 65%, 53% and 29%, respectively. Although risk factors have been defined, the impact of transplantation on relapse and survival in affected patients is not clear. Related Donor Allogeneic HSCT: Ph There are no trials in the field of HSCT in which patients with a suitable sibling-matched donor have been randomized to an allogeneic HSCT or chemotherapy. Genetic randomization or assignment, along with intent-to-treat analyses, have been the established methods of comparing allogeneic HSCT with chemotherapy treatment. 12 Gupta and colleagues 13 at the Princess Margaret Hospital reported a small single-institution series in which adult patients with ALL in CR1 age 55 years or younger were offered a myeloablative allogeneic HSCT. They found no difference in Figure 1. Probability of disease-free (DFS) and overall survival (OS) for standard-risk adult acute lymphoblastic leukemia patients. Patients are further stratified into lowrisk (LR), intermediate-risk (IR) and high-risk (HR) as determined by extent of minimal residual disease. Reprinted with permission from Brüggemann M, et al. Blood 2006;107: Hematology outcome between the donor versus no-donor groups. Highrisk adults in CR1 (which included Ph + patients) who had a sibling matched-related donor (MRD; N = 41) were assigned a myeloablative allogeneic HSCT, while the others proceeded to an autologous HSCT (N = 115) in the GOELAMS-02 trial. 14 Six-year DFS and OS were statistically superior in those who underwent allogeneic HSCT, 75% versus 39% (P =.0027). The French LALA group has addressed this question prospectively in their LALA-94 trial. 15 Because of the suggestion of a benefit in LALA-87 to allogeneic HSCT in patients under age 55 years who did not have standard-risk disease, 3 they designed a trial of risk-adapted postremission strategy in adult ALL. Patients ages 15 to 55 years with any high-risk ALL features and an HLA-identical sibling were assigned to allogeneic HSCT. Five-year DFS in the group with Ph high-risk ALL in first CR was improved in the allogeneic HSCT (45% vs 23%, sibling donor vs those with no sibling donor). In multivariate analysis, both age and WBC count were found to be prognostic factors for DFS; however, the impact on the two groups (donor vs no donor) was not discussed. In the largest trial reported to date (MRC-ECOG UKALLXII/E2993), 1826 adult patients with ALL were given induction therapy that resulted in a 91% CR rate. 1 All patients younger than 50 years old, irrespective of risk, with a sibling MRD were recommended to undergo a myeloablative HSCT using a total body irradiation (TBI) containing conditioning regimen. 16 For 919 patients in CR, 389 with a donor were compared with 524 patients with no donor (Table 1). Event-free survival (EFS) and OS were statistically superior in the donor group: 50% versus 41% (P =.009) and 53% versus 45% (P =.02). As noted historically with most HSCT reports, in general, the optimal allogeneic effect for EFS and OS were observed in the standard-risk rather than the high-risk group (where high risk was defined by age and WBC count). Although in both risk groups the relapse rates were significantly lower in the donor group compared with the no donor group, supporting a Table 1. MRC-ECOG UKALLXII/EC2993: outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in Ph patients who had donors versus those who did not have donors. 5-y 5-y 2-y overall relapse nonrelapse No. survival, % rates, % mortality, % High-risk* 401 Donor No donor Standard-risk 512 Donor No donor * High-risk is defined as age 35 years, WBC 30,000/µL for patients with B-cell disease or WBC 100,000/µL for patients with T-cell disease, or time to attain CR 4 weeks. strong GVL effect, the TRM rates at 2 years were significantly increased in the high-risk group, 39% versus 20%. Such findings, in large part, reflect poor tolerance to a myeloablative conditioning regimen in those patients older than 35 years. Thus, the majority of the data in Ph patients favor an improved outcome in younger patients who underwent a MRD allogeneic HSCT, an effect lost when older patients are conditioned using a myeloablative regimen. The number of patients with sibling donors, however, far exceeds the usual ratio of success in finding HLA-matched siblings (such as observed in acute myeloid leukemia HSCT trials). Although the number of patients with a donor appears high, it is consistent with some of the previously published ALL HSCT studies. For example, in the LALA- 94 study, for the high-risk group 100 patients had a donor compared with 159 without a donor. 15 Table 2 compares several large trials for ALL CR1 patient outcome. These and other data support the use of a MRD myeloablative allogeneic HSCT for the 32-year-old woman in CR1 described in Case 1. Due to advanced age, however, the 64-year-old man described in Case 2 is not a viable candidate for a MRD myeloablative allogeneic HSCT. Allogeneic HSCT: Ph + Although Ph + patients have a lower remission rate and higher relapse rate using conventional chemotherapy compared to those with Ph disease, allogeneic HSCT is particularly effective in Ph + patients. Dombret and co-workers 17 reported the LALA-94 trial data for 154 Ph + patients who proceeded to transplant (N = 103) after attainment of CR1. Sixty patients who underwent allogeneic HSCT (n = 46 MRD and n = 14 MUD) had the same 2-year TRM as 43 patients who underwent autologous HSCT, but OS at 3 years was significantly superior, 37% versus 12% (P =.02). Attainment of BCR-ABL negative status conferred a significantly better OS as well, 54% versus 12% (P =.006). The French Bone Marrow Transplantation Society 18 reported outcome of 121 patients with Ph + ALL, including 102 adults, of whom 76 were in CR1 at time of transplant. Two-year OS in the CR1 patients was 50% and the 2-year relapse incidence rate was 37%. Stirewalt and colleagues 19 at the Fred Hutchinson Cancer Research Center retrospectively analyzed 90 patients with Ph + ALL aged 2 to 56 years (median, 33 years) who underwent myeloablative allogeneic HSCT. Morphologic or cytogenetic evidence of ALL at time of transplantation as well as autologous or MRD use predicted for highest risk of relapse, while development of chronic graft-versus-host disease (GVHD) after transplantation lowered the relapse rates. These investigators proposed that patients without molecular evidence of disease ( low risk ) undergo a less intense (nonmyeloablative) HSCT. They advocated a more aggressive conditioning be used in high-risk patients who have minimal residual or overt disease at time of transplantation including consideration of post-transplantation imatinib consolidation. Gupta and coworkers 13 reported a study in which unrelated donor 446 American Society of Hematology Table 2. Comparison of several large trials for acute lymphoblastic leukemia (ALL) CR1 patient outcome. No. pts. Group Study, considered Outcome Chemo- Autologous Allogeneic citation for HSCT measure therapy, % HSCT, % HSCT, % P MRC-ECOG OS at 5 y JALSG-ALL OS at 6 y NS LALA OS at 10 y LALA-87 high-risk OS at 10 y LALA DFS at 3 y LALA-94 high-risk OS at 5 y but median Not stated OS not reached GOELAMS 02 high-risk OS at 6 y 40 at 6 y 75 at 6 y.0027 PETHEMA 93 high-risk OS at 5 y Abbreviations: OS, overall survival; HSCT, hematopoietic stem cell transplantation; NS, not significant (URD) allogeneic HSCT was offered to a small number of patients with Ph + ALL in CR1. Three-year DFS and OS were 46% and 57%, respectively; OS did not differ when compared with those Ph patients at their center who underwent allogeneic HSCT. Finally, in the largest prospective allogeneic HSCT study (conducted during the preimatinib era), 5-year OS was superior in those who underwent MRD allogeneic HSCT compared with chemotherapy or autologous HSCT. 20 Early relapse, prior to transplantation, however, was common supporting referral for allogeneic HSCT as soon as possible after attaining CR. 20 These and other data suggest that allogeneic HSCT provides significant GVL effect in CR1 patients with Ph + ALL. The addition of imatinib to the armamentarium for treating Ph + ALL has significantly improved the CR rate from approximately 60% to 90% and has greatly enhanced the access of such patients to allogeneic HSCT by reducing early pretransplantation relapses, a large problem in the past. Yanada et al 21 recently reported a significantly improved OS in 49 adult patients with Ph + ALL who were given post-transplantation imatinib therapy compared with historic controls, i.e., 1-year EFS and OS, 60% and 76%, respectively. Although median follow-up was short at 1 year, both patients who underwent allogeneic HSCT recipients and patients who did not had significantly better outcome. Further, imatinib appeared to prevent earlier relapse, enabling a greater percentage of patients to proceed to allogeneic HSCT. de Labarthe and coworkers 22 similarly showed that imatinib in combination with conventional chemotherapy provided results comparable with allogeneic HSCT. On the other hand, Pfeifer, for the GMALL, recently reported the prevalence of kinase domain mutations in newly diagnosed and imatinib-naive Ph + ALL. 23 BCR-ABL mutations conferring high-level imatinib resistance were present in a substantial proportion of patients with de novo Ph + ALL and eventually gave rise to relapse. These data support the recommendation to search for a wellmatched donor in this population. Until there are published reports of larger studies with longer follow-up, imatinib therapy cannot be considered the standard treatment, and allogeneic HSCT, in general, remains the preferred approach in this subgroup of patients. Imatinib s positive effect on pretransplantation PCR status, i.e., rendering patients tumor-negative before transplantation, could improve outcome. One can speculate, however, that in the post-transplantation setting, imatinib therapy is only likely to provide time until a GVL effect can develop to eradicate disease. Prophylactic imatinib after HSCT can be given safely. 24 Blood Versus Marrow as the Stem Cell Source Blood has nearly supplanted bone marrow as the hematopoietic cellular graft source for patients who undergo allogeneic HSCT. Ringden and the EBMT 25 reported a retrospective analysis of their observational database in which they compared outcome for 826 patients (513 in CR1) given marrow versus 345 patients (189 in CR1) given blood after conditioning. Engraftment, as anticipated, was faster with blood, but also resulted in an increased risk of chronic GVHD. LFS and OS did not differ among the groups. In a subsequent retrospective EBMT analysis, blood stem cell grafts obtained from URD were associated with inferior outcome compared with bone marrow grafts in ALL. 26 The incidence of 2-year TRM in 36 patients receiving blood grafts was 61% compared with 47% in 66 bone marrow recipients, resulting in significantly inferior 2-year LFS (32% vs 21%) and OS (34% vs 24%) rates, P =.04. Finally, Dahlke et al 27 reported a single-center, donor-source comparison in ALL allogeneic HSCT (46 MRD vs 38 URD). Younger patients had a significantly lower TRM, but the relapse rates did not differ, indicating similar antileukemic efficacy. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has an ongoing, prospective, randomized clinical trial examining URD blood versus marrow source grafts after myeloablative HSCT. Current data in adults do not indicate definitively that one graft source is superior; however, due to significantl
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